title: Glycogen synthase kinase-3 inhibitors augment TRAIL-induced apoptotic death in human hepatoma cells.
abstract: Hepatocellular carcinoma (HCC) displays a striking resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Therefore, the characterization of pharmacological agents that overcome this resistance may provide new therapeutic modalities for HCC. Here, we examined whether glycogen synthase kinase-3 (GSK-3) inhibitors could restore TRAIL sensitivity in hepatoma cells. To this aim, the effects of two GSK-3 inhibitors, lithium and SB-415286, were analyzed on TRAIL apoptotic signaling in human hepatoma cell lines in comparison with normal hepatocytes. We observed that both inhibitors sensitized hepatoma cells, but not normal hepatocytes, to TRAIL-induced apoptosis by enhancing caspase-8 activity and the downstream recruitment of the mitochondrial machinery. GSK-3 inhibitors also stabilized p53 and the down-regulation of p53 by RNA interference abolished the sensitizing effect of lithium on caspase-3 activation. Concomitantly, GSK-3 inhibitors strongly activated c-Jun N-terminal kinases (JNKs). The pharmacological inhibition of JNKs with AS601245 or SP600125 resulted in an earlier and stronger induction of apoptosis indicating that activated JNKs transduced protective signals and provided an anti-apoptotic balance to the pro-apoptotic effects of GSK-3 inhibitors. These findings demonstrate that GSK-3 exerts a negative and complex constraint on TRAIL apoptotic signaling in hepatoma cells, which can be greatly alleviated by GSK-3 inhibitors. Therefore, GSK-3 inhibitors may open new perspectives to enhance the anti-tumor activity of TRAIL in HCC.
authors.affiliation: UPMC Univ Paris 06, UMR_S 893, F-75005, INSERM, UMR_S 893, Centre de Recherche Saint-Antoine, F-75012, Paris, France.
authors.forename: Eléonore
authors.initials: E
authors.lastname: Beurel
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Blivet-Van Eggelpoël
authors.forename: Michel
authors.initials: M
authors.lastname: Kornprobst
authors.forename: Sylviane
authors.initials: S
authors.lastname: Moritz
authors.forename: Roland
authors.initials: R
authors.lastname: Delelo
authors.forename: François
authors.initials: F
authors.lastname: Paye
authors.forename: Chantal
authors.initials: C
authors.lastname: Housset
authors.forename: Christèle
authors.initials: C
authors.lastname: Desbois-Mouthon
mesh_terms: D000627:Aminophenols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004357:Drug Synergism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D008301:Maleimides / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; D008094:Lithium; D038362:Glycogen Synthase Kinase 3